[p53 activation by PI-3K family kinases after DNA double-strand breaks].

p53 plays a central role in the cellular response to DNA double-strand breaks (DSBs), and to DNA damage in general. The protein kinases ATM, ATR and DNA-PK detect DSBs and transmit this information to p53 by phosphorylation. This phosphorylation dissociates p53 from its negative regulator, mdm2.

High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer.

ATM mutations predispose cells to malignancy by promoting chromosomal instability. We have identified a family with multiple cancers that segregates a mutant allele of ATM, IVS61+2insTA, which causes skipping of exon 61 in the mRNA, as well as a previously undescribed polymorphism, IVS61+104C(54):T(46). The mutation was inherited by two sisters, one who developed breast cancer at age 39 and the second at age 44, from their mother, who developed kidney cancer at age 67.

ATM heterozygote cells exhibit intermediate levels of apoptosis in response to streptonigrin and etoposide.

Ataxia-telangiectasia (A-T) is a rare recessive disease characterised by cerebellar ataxia, immunodeficiency, sensitivity to ionising radiation and increased cancer risk. Heterozygotes have an increased risk of cancer and may comprise 1% of the population. In vitro, A-T heterozygote cell lines show radiosensitivity intermediate between normal and A-T homozygotes.

Loss of heterozygosity at the ATM locus in colorectal carcinoma.

Patients homozygous for mutation of the ATM gene exhibit constitutional genetic instability and have a high risk of cancer. A-T heterozygotes also have an increased tendency to develop adenocarcinomas. Colorectal cancer (CRC) is the second most common cancer in western populations, and tumors of the right colon are typically highly genetically unstable.